The invention relates to cancer therapy.
Despite advances in the identification of chemotherapeutic agents for inhibiting the growth of cancer cell, cancer remains a formidable disease with a high mortality rate. A significant problem of chemotherapeutic agents is low specificity. Many anticancer agents do not adequately distinguish normal cells from cancer cells. As a result, they often carry undesirable serious side effects.
The invention provides a method of inhibiting tumor growth in a mammal with few or no deleterious side effects. For example, the method is carried out by administering to the mammal composition containing a non-naturally-occurring taurine compound. For example, the compound is chemically synthesized. A taurine compound is a composition, which contains a taurine moiety (Sxe2x80x94Cxe2x80x94Cxe2x80x94N) but is not a metabolite of taurolidine or taurultam. Preferably, the compound does not contain a methylol moiety, nor does it produce a methylol moiety in an aqueous environment. A taurine compound contains a Sxe2x80x94Cxe2x80x94Cxe2x80x94N backbone but differs from naturally-occurring taurine in that at least substituent is altered compared to naturally-occurring taurine. The compound does not contain an ring structure or an aromatic group, i.e., it is acyclic. For example, the Sxe2x80x94Cxe2x80x94Cxe2x80x94N backbone is not part of a ring structure. Alternatively, the compound contains at least one aromatic group. The compounds differ from taurine by the addition of a substituent (e.g., an azide substituent) on a sulfur or by the addition of a substituent on a nitrogen in the backbone structure. For example, the hydrogens of an amine group are replaced with nitrogens, resulting in the substitution of an amine group with an azide group.
Tissue containing a tumor is contacted (in vivo or ex vivo) with a composition containing a taurine compound. The compound is administered directly or indirectly to contact a tumor cell at a dose sufficient to inhibit growth of tumor cells and/or induce cell death. Preferably the compound is administered in a manner and at a dose which preferentially induces apoptotic death of tumor cells compared to non-tumor (i.e., normal) cells. The compound inhibits proliferation of tumor cells. Preferably the taurine compound is characterized as having a R1xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94R2 backbone in which R1 and R2 are, independently, an alkyl, aryl, hetero group, or hydrogen. 
For example, compound is a sulfonamide derivative. Most preferably the compound is an azide derivative, such as xcex2-Azidoethanesulfonyl azide (BC-701). Preferably, the compound is not taurolidine or taurultam. 
A sulfonamide compound is one having a R2Nxe2x80x94SO2Rxe2x80x2 formula, an azide compound is one having an N3 formula. The compounds described herein differ structurally from taurine or taurinamide. The compounds have reduced toxicity, prolonged clinical half-life, or improved ability to cross the blood-brain barrier.
The compounds are cytotoxic; the level of cytotoxicity is at least 20% that of taurolidine. Preferably, the compound has at least 40%, 50%, 75%, 85%, 95%, 99% or 100% of the cytotoxic activity of taurolidine. In some cases, the cytotoxic activity of the compound exceeds the level of activity of taurolidine. Cytotoxicity is measured using a variety of standard methods, e.g., detecting the level apoptosis in a treated cell population by flow cytometry or Western blot analysis.
The compounds are antibacterial; the level of antibiotic activity is at least 20% that of taurolidine. Preferably, the compound has at least 40%, 50%, 75%, 85%, 95%, 99% or 100% of the antibiotic activity of taurolidine.
A method of treating an autologous tumor, e.g., a tumor of the central nervous system (CNS), is carried out by contacting a mammalian tumor cell with a taurine compound. For example, the compound is administered to a mammal, e.g., a human patient,. Tumors to be treated include solid tumors, non-solid tumors, and lymphomas. For example, the autologous tumor is a breast cancer, ovarian cancer, colon cancer, prostate cancer, pancreatic cancer, CNS cancer, liver cancer, lung cancer (e.g., mesothelioma), urinary bladder cancer, lymphoma, leukemia, or sarcoma. Tissue containing a tumor is directly or indirectly contacted with the compound., e.g., the compound is administered locally into a tumor site or is administered systemically to the animal.
For tumors of neurological origin, the compound is administered systemically, e.g., orally or intravenously, or infused directly into the brain or cerebrospinal fluid. Other means of drug delivery include an erodible or resorbable solid matrix such as a wafer or sponge, which is implanted directly into brain tissue. Preferably, the tumor is a glioma, astrocytoma, neuroblastoma, or CNS metastasis from a non-CNS primary tumor.
The taurine compound is administered alone or in combination with a second antineoplastic agent. For example, an antimetabolite, a purine or pyrimidine analogue, an alkylating agent, crosslinking agent (e.g., a platinum compound), intercalating agent, and/or an antibiotic is administered in a combination therapy regimen. The coadministered drug is given before, after, or simultaneously with the taurine compound. An advantage of such a combination therapy approach is that a lower concentration of the second neoplastic is required to achieve tumor cell killing.
The invention also includes treating a drug resistant tumor, e.g., a multiple drug resistant (MDR) tumor, in a mammal by administering to the mammal a taurine compound. The tumor to be treated is a carcinoma or sarcoma. The drug resistant tumor is selected from the group consisting of a solid tumor, a non-solid tumor, and a lymphoma. For example, the drug resistant tumor is a breast cancer, ovarian cancer, colon cancer, prostate cancer, pancreatic cancer, CNS cancer, liver cancer, lung cancer, urinary bladder cancer, lymphoma, leukemia, or sarcoma.
Any neoplastic cell can be treated using the methods described herein. Preferably, the taurine compound, e.g., xcex2-Azidoethanesulfonyl azide, is administered in a manner which allows direct contact of the surface of the tumor cell with the compound. Tumors to be treated include but are not limited to leukemia, lymphoma, breast cancer, ovarian cancer, colon cancer, prostate cancer, pancreatic cancer, CNS cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, urinary bladder cancer, sarcoma, and melanoma. For example, bladder cancer is treated by inflating the bladder with a solution containing a taurine compound, and skin cancers such as basal cell carcinomas or squamous cell carcinomas are treated by applying a taurine compound formulated as a film, cream, or ointment, directly to the affected skin area. For treatment of primary liver cancers or liver metastases, the compounds are infused into the hepatic artery, portal vein, or other blood vessel of the liver. Alternatively, slow release of the compound to any tissue is accomplished by implanting a drug loaded matrix in direct contact or adjacent to the tumor site.
To purge a mixed population of cells, e.g., a patient derived sample of bone marrow cells or peripheral blood cells, of contaminating cancer cells, the bone marrow cells or peripheral blood cells are cultured in the presence of a taurine compound such as xcex2-Azidoethanesulfonyl azide. The ex vivo treated cells are then washed and expanded in culture or infused into a mammalian recipient. e.g., the individual from which the cells were derived or another mammalian recipient. The number of tumor cells in the mixed population is reduced by at least one, preferably at least two, more preferably at least three, more preferably at least four, and most preferably at least five log units, after treatment.
The taurine compounds are formulated for administration to directly contact cancer cells, e.g., in the form of an aqueous solution. Formulations include a therapeutic film-forming composition containing or coated with a taurine compound as well as ointments, pastes, sprays, patches, creams, gels, sponges, and foams.
Other features and advantages of the invention will be apparent from the following detailed description and from the claims.